Even for patients who have maintained long-term abstinence from drugs, relapse remains a substantial risk. As we have shown using ecological momentary assessment (EMA), lapses to drug use may follow acute increases in stress. In the rat reinstatement model of relapse, stress-induced seeking of heroin, cocaine, speedball (heroin-cocaine combination), alcohol, or nicotine is blocked by alpha-2 adrenoceptor agonists such as lofexidine, guanfacine, and clonidine. Thus, alpha-2 agonists may act on a final common pathway of stress-induced relapse, relevant to multiple drugs of abuse. In a randomized, placebo-controlled laboratory study, with non-treatment-seeking cocaine users, we have shown that clonidine was effective in reducing stress-induced (and, at a higher dose, cue-induced) craving in a pattern consistent with the findings from the reinstatement model. We have now taken that finding much further, having just run a clinical trial in which we showed that lapse prevention can be a major new use for an old medication, clonidine. In that trial, we also incorporated EMA as an outcome measure to test hypotheses about clonidines behavioral mechanism of action. We enrolled 208 opioid-dependent outpatients at our buprenorphine clinic. Participants who maintained abstinence continuously for 2 weeks (118, 57%) were continued on buprenorphine and randomized to clonidine or placebo for 14 weeks, double-blind. Urine was tested thrice weekly. Lapse was defined as any opioid-positive or missed urine; relapse, as consecutive lapses. Time to lapse and relapse were examined with Cox regressions; longest period of abstinence, with a t-test; EMA data, with generalized linear mixed models. In an intent-to-treat analysis, clonidine significantly increased the longest duration of consecutive days of abstinence for opioids during intervention. There was no group difference in time to relapse, but the clonidine group took significantly longer to lapse. EMA self-reports collected in the participants natural environments showed that daily-life stress was partly decoupled from opioid craving in the clonidine group, supporting our hypothesized mechanism for clonidines benefits. Thus, clonidine is useful in opioid dependence not just for alleviation of withdrawal signs, but also as an adjunct maintenance treatment that increases duration of abstinence: even in the absence of physical withdrawal, it decouples stress from craving in everyday life. We are also evaluating the role of stress in relapse in a large natural-history study in which real-time field monitoring of stressor exposure is combined with continuous location tracking via GPS. Preliminary analyses suggest some unexpected relationships between neighborhood environment and self-reported stress. As we collect more data, we should be able to determine how patterns of environmental-stressor exposure predict relapse. One of our goals is to supplement our ambulatory assessments with on-the-spot feedback, turning them into mobile interventions.